Rheumatoid arthritis is a potentially crippling autoimmune disease that affects more than two million Americans. Generally arthritis drugs may be divided into two categories: NSAID (Non-steroidal Anti-Inflammatory Drug) and DMARD (Disease Modifying Anti-Rheumatic Drug). Leflunomide is a DMARD sold as Aravas by Aventis Pharmaceuticals. Unfortunately, it is associated with many side effects, such as elevated liver enzymes; liver damage was blamed for some fatal cases. In order to discover and develop a better drug for Rheumatoid Arthritis, we have made a series of compounds based on Leflunomide and our proprietary compound (compound A) and performed in vivo inhibition studies for inflammation induced by carrageenan. Based on the anti-inflammation results, we have selected three most promising compounds (UTL-5b, UTL-5d, and UTL-5g) as potential drug candidates for treating Rheumatoid Arthritis. We also performed a preliminary LD50 study and obtained very promising results for these three compounds. We are proposing to perform this Phase I study to further understand and validate the anti-inflammatory and immunosuppressant effect in vitro for these three compounds. At the end of this Phase I study, we will be able to select the most appropriate drug candidates among the three compounds and prepare for the Phase II application. The specific aims of this Phase I study are: (a) Synthesis of about 500 mg each of three selected drug candidates. (b) Develop and validate a stability-indicating HPLC method for each compound. (c) Study the anti-inflammatory effects of the compounds on primary cultures of macrophages in vitro. (d) Study the in vitro immunosuppressant effect of the three drug candidates. The proposed Phase I and Phase II are only the beginning of a long journey to developing a new drug for rheumatoid arthritis. However, if the Phase I and Phase II are successful, the project will be essentially ready for an IND filing to the Food and Drug Administration (FDA), and large pharmaceutical companies are more likely to co-develop this project. Ultimately, the successful drug candidate will provide a significantly improved therapy for patients suffering from Rheumatoid Arthritis.